Postsynaptic 5‐hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex

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Abstract
5‐Hydroxytryptamine (5‐HT) plays a role in the regulation of 3,4‐dihydroxyphenylethylamine (dopamine) neurons in the brain, but the precise mechanism of regulation by 5‐HT1A receptors of dopamine release has not been defined. The present study describes the effect of 5‐{3‐[[(2S)‐1,4‐benzodioxan‐2ylmethyl]amino]propoxy}‐1,3‐benzodioxole HCl (MKC‐242), a highly potent and selective 5‐HT1A receptor agonist, on dopamine release in the prefrontal cortex using microdialysis in the freely moving rat. Subcutaneous injection of MKC‐242 (0.3–1.0 mg kg−1) increased extracellular levels of dopamine in the prefrontal cortex. The effect of MKC‐242 in the prefrontal cortex was antagonized by pretreatment with the selective 5‐HT1A receptor antagonist, N‐[2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl]‐N‐(2‐pyridinyl)cyclohexanecarboxamide (WAY100635; 1 mg kg−1, i.p.). Local application of WAY100635 (10 μM) via a microdialysis probe antagonized the effect of systemic MKC‐242 in an increasing dopamine release, and locally infused 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (10 μM) increased dopamine release in the prefrontal cortex. MKC‐242 increased cortical dopamine release in the rats pretreated with 5,7‐dihydroxytryptamine (150 μg, i.c.v.) that caused an almost complete reduction in cortical 5‐HT content. The effect of MKC‐242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens. Fluoxetine, a selective serotonin reuptake inhibitor, increased dopamine release in the prefrontal cortex, but not in the nucleus accumbens, while buspirone, a 5‐HT1A receptor agonist, increased dopamine release in both brain regions. The present results indicate that activation of postsynaptic 5‐HT1A receptors increases dopamine release in a brain region‐specific manner. British Journal of Pharmacology (2000) 129, 1028–1034; doi:10.1038/sj.bjp.0703139